This invention relates generally to dermatological compositions and methods for their use. More specifically, the invention relates to dermatological compositions based upon acidic amino acids. Most specifically, this invention relates to dermatological compositions based upon carboxylated, acidic amino acids.
A large variety of materials and compositions has been employed for the topical treatment of skin conditions caused by drying, photodamage, aging, acne and the like. In addition to being effective and safe, any product used for the treatment of skin conditions should be convenient to formulate, easy to use, have long term stability, and be easy to handle. Additionally, such products should preferably be low in cost.
Retinoic acid, and other retinoid compounds are effective for treating acne, wrinkles and other skin conditions. However, these materials can be very toxic and must be used under close medical supervision, and hence are prescription medications. In addition, retinoids are expensive. Strongly corrosive materials such as phenol, mineral acids and halocarboxylic acids such as trichloroacetic acid have also been used to treat damaged skin. Such corrosive materials achieve a therapeutical effect by causing the outer layers of skin to peel away. These materials must also be used under medical supervision since they can produce serious damage if misapplied.
A number of formulations have been developed for dermatological preparations, using alpha hydroxy acids and alpha keto acids. These acids are used at fairly high concentrations, in clinical settings, to produce superficial peeling of the skin. They are also used at lower concentrations by consumers and paraprofessionals to smooth and condition the skin and reduce wrinkles. In many instances, these materials can still be irritating, and as a result, compositions have been developed wherein buffering agents such as amphoteric compounds or alkaline materials have been added to the acids to raise their pH. Such compositions are shown in U.S. Pat. Nos. 4,105,782; 4,105,783 and 5,091,171. In other instances, skin care compositions have been formulated utilizing ascorbic acid, and such compositions are shown in U.S. Pat. Nos. 4,983,382 and 5,140,043.
In yet other instances, skin care compositions have been prepared utilizing relatively neutral species such as salts. PCT Patent Application WO96/19182 discloses the use of inorganic salts, primarily of magnesium, manganese and various lanthanide elements, for reducing skin irritation. U.S. Pat. No. 5,478,560 discloses the use of salts of mixed amines for treating dry skin.
As can be seen, there is a very large body of prior art directed to topical treatments for various dermatological conditions. The efficacy and safety of the various prior art compositions vary widely as do the cost and ease of formulating and using the compositions. Thus, there is still a need for a composition for treating dermatological conditions, which composition is effective, safe, easy to formulate and use and low in cost.
The parent patent, referred to hereinabove, discloses the fact that certain alpha amino acids (including those referred to as acidic amino acids) are beneficial compounds for the treatment of skin conditions. The parent patent further discloses the use of various acids, including carboxylic acids, to solubilize the amino acid compounds so as to facilitate their incorporation into various dermatological compositions. As will be described in greater detail hereinbelow, it has now been found that when acidic amino acids are solubilized with carboxylic acids, a beneficial interaction occurs which creates a new therapeutic species generally referred to herein as xe2x80x9ca carboxylated, acidic amino acidxe2x80x9d or a xe2x80x9ctricarboxylic acidxe2x80x9d or an xe2x80x9camino fruit acid.xe2x80x9d This new therapeutic material is highly effective for treating a variety of skin conditions. It has a strong antioxidant action; and, it is most surprising that, the material is very non-caustic to skin even at very low pH levels. As will be described hereinbelow, the present invention provides a composition which has very good utility for treating skin conditions associated with dryness, aging, photodamage such as photopigmentation and keratoses as well as acne and seborrheic keratoses. These and other advantages of the present invention will be apparent from the discussion and description which follow.
There is disclosed herein a composition for the treatment of skin. The composition is based upon carboxylated, acidic amino acids obtained by treating an acidic amino acid with a carboxylic acid. Some of the preferred acidic amino acids comprise alpha amino dicarboxylic acids, with aspartic and glutamic acid being some particularly preferred acidic amino acids. The carboxylic acids used in this invention can include dicarboxylic acids, hydroxy carboxylic acids, halocarboxylic acids and the like.
The present invention also concerns a method for formulating the therapeutic compositions; and in accord with the method, an acidic amino acid is reacted with a carboxylic acid to produce the carboxylated, acidic amino acid. The resultant material is disposed in an appropriate carrier, preferably in an amount sufficient to produce a composition with a pH in the range of 0.5 to 5. Also disclosed are therapeutic methods which employ the composition of the present invention.
In accord with a first aspect of the present invention, it has been found that certain amino acids have a very beneficial therapeutic effect on the skin. The compositions of the present invention improve the tone and texture of the skin and decrease wrinkling due to drying and aging. The compositions also decrease photodamage to the skin such as photopigmentation and solar keratoses, and the compositions also operate to remove or decrease the severity of acne and seborrheic keratoses. Among the preferred amino acids are the alpha amino acids and within the context of this disclosure it is to be understood that alpha amino acids are those acids in which the amine group is on the carbon which is alpha to the carboxylic acid moiety. In general, alpha amino acids have the formula set forth hereinbelow: 
wherein the R groups are independently alkyl, aryl, heterocycles, or hydrogen. It is believed that the alpha configuration results in a beneficial chemical interaction between the amino acid and the skin.
Among some of the most preferred alpha amino acids are the alpha amino dicarboxylic acids. As will be understood by those of skill in the chemical arts, alpha amino dicarboxylic acids are those amino acids having two carboxyl groups, and in which the amine group is alpha to at least one of the carboxyl groups. Two of the particularly preferred alpha amino dicarboxylic acids which may be employed in the practice of the present invention are aspartic acid, shown at Formula 2 hereinbelow, and glutamic acid, shown at Formula 3 hereinbelow. 
It is to be understood that these amino acids may be also present as salts or ions.
The materials of the present invention are of very low toxicity, and are relatively nonirritating to the skin; hence, they may be used in very high concentrations. However, it has been found that in most instances, amino acid concentrations ranging up to 20%, by weight, are generally effective. In those situations where the composition is being employed in a clinical setting, and particularly when keratoses and other such conditions are being addressed, relatively high concentrations of the composition will be employed. In those instances where the material is being utilized in a nonclinical setting and/or relatively minor conditions are being treated, lower concentrations will suffice. Typically, concentrations of amino acids in the range of 0.5-20% are employed, with concentrations in the range of 2-3% being sufficient for many treatment plans.
The amino acids of the present invention are disposed in a carrier, which in the simplest case comprises water. In other instances, water or alcohol based lotions as well as creams, ointments, gels and other such pharmaceutically acceptable carriers may be utilized. As is known in the art, carriers may further include fragrances, emollients, coloring agents, preservatives, and the like.
In some instances, the alpha amino acids of the present invention are of relatively low solubility in water, weak acids or alcohol. In addressing this problem, it has been found that further enhancements to the compositions of the present invention may be achieved if the alpha amino acid is first dissolved in a solvent system which includes a strong acid therein. As is known in the art, and within the context of this disclosure, strong acids are those acids which are highly ionized in solution and are generally categorized as having a dissociation constant (KA) which is greater than 1. Trichloroacetic acid is one strong acid which is preferably employed in the practice of the present invention. Other strong acids comprise other halocarboxylic acids such as fluoroacetic acids as well as mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid and the like.
In accord with this aspect of the present invention, the alpha amino acid is first dissolved in the solvent system which includes a strong acid therein. For example, it has been found that solutions of up to 20%, by weight, of trichloroacetic acid are highly effective solvents for aspartic acid, which is one of the particularly preferred alpha amino acids of the present invention. After the solution of the alpha amino acid is complete, at least a portion of the remaining strong acid in the solution is neutralized so as to raise the pH of the solution to a therapeutically preferred range. Typically, this range is from approximately 0.5 to approximately 5, and it has been found that the solubilized alpha amino acids remain in solution, in relatively high concentrations, at this pH range. In those instances where the composition of the present invention is being employed in a clinical setting, under professional supervision, relatively low pHs of 0.5 to 2.0 may be effectively employed. In those instances where compositions are being prepared for use in a home, or other nonprofessional setting, relatively higher pHs in the range of 2 to 3 are typically employed. In some instances, effective, stable compositions may be prepared having pHs as high as 5.
Neutralization of the acid may be carried out using any basic material which is compatible with the solvent system and physiologically acceptable. One particularly preferred base comprises urea, and it is believed that the urea, or any resultant salt of urea, further enhances the therapeutic effect of the composition. Other bases which may be advantageously employed are purines, as well as amines. Ammonium hydroxide may also be effectively employed as a base, as may be inorganic bases such as sodium hydroxide and other alkali metal hydroxides.
While not wishing to be bound by conjecture, the inventor speculates that it is possible that the strong acid solubilization and/or neutralization steps may produce new chemical species which further enhance the efficacy of the alpha amino acids of the present invention. Such enhancement may come from the formation of salts or from a chemical rearrangement of the amino acid, as for example by the addition of further carboxyl groups thereto, or by the formation of esters, imines, imides, amides and other such species.
In the broadest sense, the compositions of the present invention are based upon the use of therapeutic compositions of alpha amino acids, and more preferably alpha amino dicarboxylic acids. In yet more specific embodiments of the invention, the compositions are prepared by a method wherein strong acids are first employed to solubilize and/or modify the alpha amino acids, and bases are then employed, as needed, to adjust the pH of the resultant composition.
In accord with still other aspects of the present invention, yet other auxiliary ingredients may be added to the compositions. For example, it has been found that ascorbic acid further enhances the efficacy of the compositions. Most typically, the ascorbic acid, if employed, is present in an amount, by weight, of up to 5% of the composition, although higher concentrations such as 20% may be employed. While there is no lower limit to the amount of ascorbic acid which may be employed, typically, if it is employed at all, it is present in an amount of at least 0.5% by weight. In a most preferred embodiment of the invention, ascorbic acid comprises, by weight, 0.5-5% of the composition. In other instances, citric acid may be included in the compositions, in similar amounts. In yet other instances inorganic salts can be added to the composition, as will be elaborated upon hereinbelow.
Yet other auxiliary ingredients may be employed in the compositions of the present invention. For example, the compositions may be formulated into a cream, gel or lotion base, using any pharmaceutically acceptable carrier. In some instances, the compositions may be formulated into a peel-off mask by employing a film forming carrier such as polyvinyl alcohol or an inorganic, mud pack type carrier such as a clay-based material. As is known in the art, colorings, fragrances, preservatives and the like may be similarly included in the compositions of the present invention.
The following are some examples of compositions in accord with the present invention.